Vepdegestrant outperforms fulvestrant in ESR1-mutant aBC

Vepdegestrant demonstrated significant improvement in progression-free survival (PFS) when compared with fulvestrant in advanced breast cancer patients (aBC) with a mutation in the oestrogen receptor 1 (ESR1) gene. However, the benefit did not extend to the broader intention-to-treat population, where the difference in PFS was not statistically significant.

Dr Erika Hamilton (Sarah Cannon Research Institute, Nashville, TN, USA) presented the initial findings of the phase 3 VERITAC-2 trial (NCT05654623) [1]. Vepdegestrant is the first PROteolysis TArgeting Chimaera (PROTAC) molecule to reach phase 3 evaluation.

In this multicentre study, 624 patients with aBC who had previously received one line of endocrine therapy plus a CDK4/6 inhibitor were randomised 1:1 to receive either vepdegestrant 200 mg orally once daily or fulvestrant 500 mg intramuscularly according to the standard schedule. Participants were stratified by ESR1 mutation status and presence of visceral disease. Patients with prior chemotherapy for advanced disease or prior fulvestrant intake were excluded.

Among the 270 participants with ESR1 mutations in their tumours (136 in the vepdegestrant arm and 134 in the fulvestrant arm), vepdegestrant significantly prolonged PFS (HR 0.57; 95% CI: 0.42–0.77; P=0.0001), corresponding to a median PFS of 5.0 months with vepdegestrant versus 2.1 months with fulvestrant.

In the overall study population of 624 participants, PFS was numerically improved with vepdegestrant, but the difference did not reach statistical significance (HR 0.83; 95% CI 0.68–1.02; P=0.0358), with a median PFS of 3.7 months versus 3.6 months for fulvestrant. The study was powered to detect a hazard ratio (HR)<0.60 in the ESR1-mutant subgroup and a HR <0.67 in the full population, with 88% and 92.5% power, respectively (one-sided α=0.01875). Overall survival data remain immature, with only 20% of events reached at the time of this analysis.

The safety profile of vepdegestrant was consistent with earlier phase data. Among 619 participants who received at least 1 dose, grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 23.4% of participants in the vepdegestrant arm versus 17.6% in the fulvestrant arm. TEAEs leading to treatment discontinuation were rare, occurring in 2.9% of participants in the vepdegestrant group and 0.7% in the fulvestrant group. The most common TEAEs in participants receiving vepdegestrant were fatigue (26.6%), increased ALT (14.4%), increased AST (14.4%), and nausea (13.5%).

These findings indicate that vepdegestrant provides a statistically significant and clinically meaningful improvement in disease control among patients with ESR1-mutant ER-positive/HER2-negative aBC, supporting its development as a potential oral, targeted therapeutic option for this genetically defined subgroup. Further data on overall survival and longer-term outcomes are awaited.

1. Hamilton EP, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomised, phase 3 VERITAC-2 study. Abstract LBA1000, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Hamilton EP, et al. Future Oncol. 2024;20(32):2447-2455.

Medical writing support was provided by Dr Rachel Giles.
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Posted on 2 June 20252 June 2025